Understanding the link between PMN-MDSCs and CXCL8-CXCR1/2 axis in primary myelofibrosis.

Emergency myelopoiesis in cancer and chronic inflammation leads to the accumulation of myeloid-derived suppressor cells (MDSCs) which localize at tumor sites or areas of chronic inflammation, serving as suppressor cells. Besides reducing the cytotoxic functions of T/NK cells, these cells are major players of the inflammatory process that characterizes the onset and progression of cancer. Inflammation is thought to play a relevant role in the progression of primary myelofibrosis (PMF) and recent studies reported an increased frequency of circulating polymorphonuclear MDSCs (PMN-MDSCs) in these patients, especially in an advanced disease stage. Here, we describe an involvement of the axes CXCL8-CXCR1/2 and, at a lesser extent, CXCL12-CXCR4 in the occurrence of circulating PMN-MDSCs in patients. Our data suggest that, in PMF patients, the persistent inflammatory stimulus promotes the upregulation of CXCR1 expression on PMN-MDSCs (P = 0.024) compared with healthy subjects (HDs). A similar expression of CXCR1 is observed in the circulation of HDs treated with G-CSF (G-HDs) where the egression of MDSCs is related to the chemokine CXCL8. Moreover, the protein levels of CXCR4, an important factor in recruiting MDSCs, are elevated on PMN-MDSCs from PMF (P = 0.02) and G-HDs (P = 0.03) compared to controls, a pattern previously observed in solid cancers. Interestingly, in G-HDs the mobilization of PMN-MDSCs is a consequence of G-CSF stimulation and transient, while in PMF it is possibly mediated by the chronic inflammatory status characterizing the disease. These findings indicate that the overexpression of two distinct membrane receptors plays a prominent role in the biology of MDSCs in PMF.